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      Effects of Antenatal Maternal Depressive Symptoms and Socio-Economic Status on Neonatal Brain Development are Modulated by Genetic Risk

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          Abstract

          This study included 168 and 85 mother–infant dyads from Asian and United States of America cohorts to examine whether a genomic profile risk score for major depressive disorder (GPRS MDD) moderates the association between antenatal maternal depressive symptoms (or socio-economic status, SES) and fetal neurodevelopment, and to identify candidate biological processes underlying such association. Both cohorts showed a significant interaction between antenatal maternal depressive symptoms and infant GPRS MDD on the right amygdala volume. The Asian cohort also showed such interaction on the right hippocampal volume and shape, thickness of the orbitofrontal and ventromedial prefrontal cortex. Likewise, a significant interaction between SES and infant GPRS MDD was on the right amygdala and hippocampal volumes and shapes. After controlling for each other, the interaction effect of antenatal maternal depressive symptoms and GPRS MDD was mainly shown on the right amygdala, while the interaction effect of SES and GPRS MDD was mainly shown on the right hippocampus. Bioinformatic analyses suggested neurotransmitter/neurotrophic signaling, SNAp REceptor complex, and glutamate receptor activity as common biological processes underlying the influence of antenatal maternal depressive symptoms on fetal cortico-limbic development. These findings suggest gene–environment interdependence in the fetal development of brain regions implicated in cognitive–emotional function. Candidate biological mechanisms involve a range of brain region-specific signaling pathways that converge on common processes of synaptic development.

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          Most cited references66

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          Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale.

          The development of a 10-item self-report scale (EPDS) to screen for Postnatal Depression in the community is described. After extensive pilot interviews a validation study was carried out on 84 mothers using the Research Diagnostic Criteria for depressive illness obtained from Goldberg's Standardised Psychiatric Interview. The EPDS was found to have satisfactory sensitivity and specificity, and was also sensitive to change in the severity of depression over time. The scale can be completed in about 5 minutes and has a simple method of scoring. The use of the EPDS in the secondary prevention of Postnatal Depression is discussed.
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            Synaptic dysfunction in depression: potential therapeutic targets.

            Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response.
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              Serotonin transporter genetic variation and the response of the human amygdala.

              A functional polymorphism in the promoter region of the human serotonin transporter gene (SLC6A4) has been associated with several dimensions of neuroticism and psychopathology, especially anxiety traits, but the predictive value of this genotype against these complex behaviors has been inconsistent. Serotonin [5- hydroxytryptamine, (5-HT)] function influences normal fear as well as pathological anxiety, behaviors critically dependent on the amygdala in animal models and in clinical studies. We now report that individuals with one or two copies of the short allele of the serotonin transporter (5-HTT) promoter polymorphism, which has been associated with reduced 5-HTT expression and function and increased fear and anxiety-related behaviors, exhibit greater amygdala neuronal activity, as assessed by BOLD functional magnetic resonance imaging, in response to fearful stimuli compared with individuals homozygous for the long allele. These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele.
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                Author and article information

                Journal
                Cereb Cortex
                Cereb. Cortex
                cercor
                Cerebral Cortex (New York, NY)
                Oxford University Press
                1047-3211
                1460-2199
                May 2017
                18 March 2017
                18 March 2017
                : 27
                : 5
                : 3080-3092
                Affiliations
                [1 ] Department of Biomedical Engineering and Clinical Imaging Research Center, National University of Singapore , Singapore 117576, Singapore
                [2 ] Singapore Institute for Clinical Sciences, Singapore 117609, Singapore
                [3 ] Departent of Medical Psychology, Charité University Medicine Berlin , Berlin 10117, Germany
                [4 ] Development, Health and Disease Research Program, Department of Pediatrics, University of California, Irvine , CA 92697, USA
                [5 ] Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University Health System , Singapore 119228, Singapore
                [6 ]Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802, USA
                [7 ] Department of Diagnostic and Interventional Imaging, KK Women's and Children's Hospital (KKH), Singapore 229899, Singapore
                [8 ] Department of Computer Science, University of North Carolina , Chapel Hill, NC 27599, USA
                [9 ] Department of Psychiatry, University of North Carolina , Chapel Hill, NC 27514, USA
                [10 ] Ludmer Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University , Montréal H4H 1R3, Canada
                [11 ] Sackler Program for Epigenetics & Psychobiology at McGill University , Montréal H4H 1R3, Canada
                Author notes
                [* ]Address correspondence to Anqi Qiu, Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore. Email: bieqa@ 123456nus.edu.sg
                Article
                bhx065
                10.1093/cercor/bhx065
                6057508
                28334351
                2be5373b-e854-46f1-ae16-07c9335bafa9
                © The Author 2017. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 18 November 2016
                : 25 February 2017
                : 28 February 2017
                Page count
                Pages: 13
                Funding
                Funded by: National Institute of Health 10.13039/100000002
                Award ID: R01 MH091351, R01 HD060628
                Funded by: National Medical Research Council 10.13039/501100001349
                Award ID: NMRC/TCR/004-NUS/2008
                Award ID: NMRC/CBRG/0039/2013
                Funded by: Hope for Depression Research Foundation 10.13039/100006346
                Funded by: Canadian Institutes for Advanced Research
                Funded by: Singapore Ministry of Education Academic Research Fund Tier 2
                Award ID: MOE2012-T2-2-130
                Categories
                Original Articles

                Neurology
                amygdala,cortical thickness,depression,morphological shape,polygenic risk score
                Neurology
                amygdala, cortical thickness, depression, morphological shape, polygenic risk score

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